Congenital long QT syndrome: Diagnosis

INTRODUCTION — 

Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) (waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death [1]. The primary symptoms in patients with LQTS include syncope, seizures, cardiac arrest, and sudden cardiac death. LQTS is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" (waveform 2) [2].

LQTS may be congenital or acquired [1,3-7]. Pathogenic variants in up to 17 genes have been identified thus far in patients with congenital LQTS; the three major genetic subtypes are designated LQT1 through LQT3 while the minor LQTS-susceptibility genes are designated by their genetic substrate (eg, CALM1-LQTS) (table 1) [7]. Acquired LQTS results from certain disease states, medications (www.crediblemeds.org), or electrolyte disturbances (table 2). (See "Congenital long QT syndrome: Pathophysiology and genetics".)

The diagnostic approach to persons with suspected congenital LQTS will be reviewed here. The epidemiology, clinical features, and management of congenital LQTS are discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Treatment".)

Acquired LQTS is discussed elsewhere. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)

WHEN TO SUSPECT CONGENITAL LQTS — 

The diagnosis of congenital long QT syndrome (LQTS) should be suspected in any patient ≤40 years of age who has one or more of the following clinical or historical features:

●History of abrupt syncope (ie, not vasovagal), sudden cardiac arrest, torsades de pointes, generalized seizures, or unexplained motor vehicle accident. Patients with cardiac arrest can present with jerking or twitching that can be mistaken for seizure.

●Family history of premature sudden death (≤40 years of age and autopsy negative), unexplained motor vehicle accident, unexplained drowning, generalized seizures, or genetically proven LQTS.

●Corrected QT interval (QTc) above the 99^th percentile (ie, QTc ≥460 ms in prepubertal patients, QTc ≥470 ms in postpubertal males, ≥480 ms in postpubertal females), assuming a normal QRS width <120 ms.

Patients with a personal or family history concerning for arrhythmia and a QTc above the 99^th percentile have a high likelihood (ie, >90 percent) of congenital LQTS. Of patients without a concerning history, those with QTc ≥480 ms (prepubertal children) or QTc ≥500 ms (postpubertal patients) have a 10 percent risk of LQTS (versus 0.05 percent in the general population).

It is important to understand that a normal QT interval does not rule out LQTS; in fact, up to 40 percent of patients with genetically proven LQTS have a normal QTc [8]. We have diagnosed LQTS even in patients with a shorter-than-average QTc. For this reason, congenital LQTS should be suspected if there is a concerning personal or family history regardless of the QTc.

REFERRAL TO A SPECIALIST — 

Patients with suspected congenital long QT syndrome (LQTS) should be referred to a specialist (eg, pediatric or adult cardiologist, cardiac electrophysiologist, genetic cardiologist) with expertise in the diagnosis of LQTS. Referral to a specialist reduces the likelihood of misdiagnosis [9,10] because the diagnostic evaluation entails clinical features that require expert interpretation (eg, electrocardiogram [ECG] findings, genetic test results, exercise test results). In some cases, the specialist may recommend consultation with a cardiovascular genetic counselor to obtain a detailed multigeneration family history and interpret genetic test results.

EVALUATION OF ALL PATIENTS — 

In all patients suspected of congenital long QT syndrome (LQTS), our initial evaluation includes obtaining a personal and family history, performing a physical examination and basic laboratory tests, and reviewing serial electrocardiograms (ECGs). The purpose of this initial evaluation is to exclude potential causes of acquired LQTS and to estimate the likelihood of congenital LQTS, which will determine whether genetic testing is indicated.

History and physical — When obtaining a history, we gather information that will be used to determine the clinical likelihood of congenital LQTS and acquired LQTS. We ask the patient and caregivers about the following elements:

●History of abrupt syncope (ie, not vasovagal syncope), syncope followed by generalized seizures, unexplained motor vehicle accidents, or resuscitated sudden cardiac arrest (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Symptoms'.)

●History or symptoms of metabolic conditions (eg, hypokalemia, hypomagnesemia, hypothyroidism, anorexia nervosa) and other conditions (eg, acute myocardial infarction, human immunodeficiency syndrome, hypothermia) that may prolong the QT interval (table 2). Examples of relevant symptoms include the following (see "Acquired long QT syndrome: Definitions, pathophysiology, and causes"):

•Muscle cramping, fasciculations, paresthesias, and perioral numbness, which may be due to an electrolyte abnormality (eg, hypokalemia, hypomagnesemia, hypocalcemia).

•Fatigue, cold intolerance, dry skin, constipation, and weight gain, which may be due to hypothyroidism.

•Chest discomfort and dyspnea, which may be due to acute myocardial infarction.

●Family history (in a first-degree relative) of premature sudden death (≤40 years of age), unexplained motor vehicle accidents, unexplained drownings, generalized seizures, or genetically proven LQTS.

●Use of medications that may prolong the QT interval (www.crediblemeds.org) (table 2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Drugs that prolong the QT interval'.)

Our physical examination focuses on findings associated with metabolic causes of acquired LQTS (table 2), including the following:

●Bradycardia, which can occur with anorexia nervosa or hypothyroidism

●Low body mass index and/or cachexia, which may be due to anorexia nervosa

●The presence of myxedema, which may be caused by hypothyroidism

●Muscle fasciculations, which can be seen with hypomagnesemia

Laboratory tests — In patients with suspected congenital LQTS, we order the following laboratory studies to rule out common causes of acquired LQTS:

●Serum potassium, magnesium, and calcium

●Thyroid-stimulating hormone with reflex-free T4

Findings of hypokalemia, hypomagnesemia, hypocalcemia, or hypothyroidism suggest that the patient may have acquired LQTS. (See 'Address reversible causes' below.)

Electrocardiogram — For patients with suspected LQTS, we carefully evaluate the QT interval on serial ECGs. The T wave morphology may also be useful, but the QTc appears to be the most useful diagnostic and prognostic parameter [11].

QT interval — The QT interval is measured from the onset of the QRS complex to the point at which the T wave ends (waveform 1). The QT interval should be measured manually using at least two leads (preferably leads II and V5) [12,13] and then corrected for heart rate. QT prolongation should be present on at least two serial ECGs because the QTc varies in response to a number of factors, such as autonomic state and diurnal changes [14,15].

The U wave should not be included if it is distinct from the T wave (ie, the T wave has returned completely to the isoelectric line) or less than one-half the amplitude of the T wave. Erroneous inclusion of the U wave in the QT interval measurement can lead to overdiagnosis of LQTS [9].

The QT interval should be adjusted based on the heart rate because the QT interval is expected to be longer at slower rates and shorter at faster rates. We typically use the Bazett formula (QTc = QT interval ÷ √RR interval [in sec]), although several other correction methods exist (calculator 1) [14,16-19]. This correction method is less accurate at heart rate extremes than at normal heart rates, resulting in overcorrection at high heart rates and undercorrection at low heart rates [14].

Atrial fibrillation and sinus arrhythmia present a challenge when measuring the QTc. To accommodate the beat-to-beat variability in the QT interval, some clinicians recommend averaging the measurements over 10 beats. Others advise measuring the QT intervals that follow the longest and shortest RR intervals in the ECG, then dividing each by the square root of the preceding RR interval [16]. The average of these two values is then used as the corrected QT interval. Still others find the measurement of QT and QTc in atrial fibrillation to be completely unreliable and instead focus on the T wave morphology characteristics. (See 'T wave' below.)

Patients with congenital LQTS rarely have a wide QRS complex. However, when QRS width is >120 ms, the width must be taken into consideration when interpreting the QTc. Several methods have been proposed to account for a wide QRS complex, but there is no consensus about which method is best. These methods are described below:

●Measurement of the JT interval (defined as the QT interval minus the QRS duration) may be an appropriate way to identify abnormalities in repolarization in patients with a wide QRS complex [20]. The normal JTc (ie, JT interval corrected for heart rate, which is calculated by the same method used for QT correction) is less than 360 ms in children without LQTS and is typically greater than 360 ms in children with LQTS [20]. However, the validity of using the JT interval in this manner is uncertain.

●A threshold of 500 ms for a prolonged QTc in the setting of a wide QRS complex has been proposed [16]. However, this threshold will result in an overdiagnosis of LQTS. Importantly, patients with congenital LQTS almost never have concomitantly prolonged QRS values.

●A simple wide QRS adjustment formula may be used: Wide QRS adjusted QTc = QTc – [QRS – 100].

●Adjustment of the QT interval as a linear function to account for QRS duration and heart rate in the setting of ventricular conduction delay has been proposed but is not generally used [21].

T wave — Certain T wave abnormalities (ie, notched T waves, biphasic T waves, T wave alternans) increase the likelihood of congenital LQTS. In one report, notched or biphasic T waves were present in 62 percent of patients with LQTS compared with 15 percent of control subjects and were associated with increased arrhythmic risk [22]. A variety of other atypical T wave shapes have also been described in patients with LQTS [23].

Address reversible causes — The history, physical examination, and laboratory tests may identify a reversible cause of QT prolongation. Most of these causes (eg, drugs, metabolic derangement) are reversible in a short timeframe, whereas others (eg, anorexia nervosa) may be more challenging to resolve. If a patient is taking a QT-prolonging drug, we hold that medication if we can safely do so. If they have a metabolic cause of QT prolongation (eg, electrolyte disorder), we correct the abnormality. We then reassess the QT interval after an appropriate time interval.

A quarter of patients with a potentially reversible cause of QT prolongation are found to have underlying congenital LQTS based on genetic testing [24]. In such patients, the QTc may be within the normal range after removal of the reversible cause; however, normalization of the QTc does not rule out underlying congenital LQTS. Thus, for most patients, we proceed with further testing (ie, exercise treadmill testing [ETT], ambulatory rhythm monitor) even if the QTc has normalized. However, for patients with QT prolongation during acute myocardial infarction and normal QTc on subsequent ECGs, we do not generally perform further testing because it is unusual for a patient to have both coronary artery disease and congenital LQTS.

It is important to address any reversible causes before proceeding with an ETT because the resting QTc will impact our interpretation of the ETT. (See 'Exercise testing' below.)

Exercise testing — For patients with suspected congenital LQTS who are capable of exercising on a treadmill, we perform an ETT. Certain findings on ETT increase the likelihood of the diagnosis. In addition, the presence of exercise-induced arrhythmias impacts prognosis and treatment [25]. (See "Congenital long QT syndrome: Treatment".)

We look for the following findings on exercise testing:

●Exercise phase – In normal individuals, the QT interval shortens as the heart rate increases. Patients with LQT1 have diminished shortening of the QT interval and a reduced chronotropic response to exercise [8,26-28], whereas others (eg, LQT2 variant) may have normal QT interval shortening and a normal chronotropic response to exercise [26,29], although there are exceptions. Exercise testing may trigger arrhythmias in patients with LQT1.

●QT interval during recovery phase – Patients with either LQT1 or LQT2 typically exhibit a maladaptive/paradoxical increase in QTc during recovery compared with the baseline QTc, while those with LQT3 do not. For patients with a normal QTc at rest, a QTc ≥470 ms throughout the first five minutes of the recovery phase is predictive of LQT1 [8]. An increase in QTc of more than 30 ms (ie, the QTc at three minutes recovery is at least 30 ms longer than the baseline QTc) is also predictive of LQT1. For patients with LQT2, the QTc at five minutes of recovery is significantly greater than at one-minute recovery; this is described as abnormal “QTc latency.”

●Heart rate recovery during recovery phase – Accentuated heart rate recovery appears to be a marker of increased risk of cardiac events (ie, syncope or aborted sudden cardiac death) in patients with LQT1. Among 169 patients with LQT1 who underwent standard exercise testing and achieved similar maximal heart rate and workloads, those with prior cardiac events had a significantly greater heart rate recovery during the first minute following exercise compared with those without prior events (19 versus 13 beats per minute in a 47 patient cohort; 27 versus 20 beats per minute in a 122 patient cohort) [30]. Patients with LQT1 who have greater heart rate reductions immediately following exercise are at a higher risk of arrhythmic events.

Exercise testing is more likely to reveal abnormal results for patients with LQT1 than other genetic subtypes of LQTS. The exercise findings in LQT1 patients occur because their pathogenic variants impair the function of the Kv7.1 outward-rectifying potassium channels, shortening the action potential during activation of the sympathetic nervous system. Cardiac events in patients with LQT1 tend to occur during exercise (figure 1) because of sympathetic activation [31]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.)

The response to exercise testing in patients with suspected congenital LQTS is frequently subtle and complex, requiring a high degree of experience to correctly interpret and diagnose the findings. If doubt exists surrounding the interpretation or implications of ECG findings postexercise, the patient should be referred to a clinician with specific expertise in congenital LQTS diagnosis. (See 'Referral to a specialist' above.)

Ambulatory ECG monitoring — We order a 24-hour ambulatory ECG monitor for all patients in whom the diagnosis of congenital LQTS is being considered [32-35]. The results of this test may be helpful for diagnosis, prognosis, or both.

The QT interval and T wave morphology may vary with activity and time of day. Ambulatory ECG monitoring can detect intermittent QT prolongation, macroscopic T wave alternans, and T wave notching [32,34,35]. QT prolongation on ambulatory monitoring should be interpreted with caution because healthy patients can have a prolonged QT interval at times, particularly when their heart rate increases rapidly [36]. We do not make the diagnosis of LQTS based solely on the QTc measurement during ambulatory recordings.

GENETIC TESTING TO ESTABLISH THE DIAGNOSIS

Deciding who should be tested — The diagnosis of congenital long QT syndrome (LQTS) is established by genetic testing [4,7,37-39]. Three genes (KCNQ1, KCNH2, SCN5A) account for 80 to 90 percent of LQTS cases. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".)

Genetic testing is reserved for patients in whom congenital LQTS is still suspected after the initial evaluation has been performed. Our approach to genetic testing is as follows:

●For patients who have a first-degree relative with a pathogenic LQTS variant identified on genetic testing, we perform variant-specific testing. This type of genetic testing is discussed in detail elsewhere. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)", section on 'First-degree relatives'.)

●For all other patients, we use the information obtained during the initial evaluation to calculate the Schwartz score, which estimates the clinical likelihood of a congenital LQTS diagnosis. The Schwartz score incorporates the QTc, T wave appearance, exercise test findings, and clinical and historical factors (eg, torsades de pointes, history of syncope, family history of LQTS, congenital deafness) [40-43]. The diagnostic criteria are assigned points as indicated in the table (table 3). The probability of a patient having genotype-confirmed congenital LQTS depends on the number of accrued points [42,43]:

•High score – If a patient has a high Schwartz score (ie, ≥3.5 points), the likelihood of a positive LQTS genetic test is high (approximately 80 percent).

•Intermediate score – A score of 1.5 to 3 points is associated with an intermediate probability of congenital LQTS.

•Low score – If the score is ≤1 point, the likelihood of congenital LQTS is low.

We take the following approach based on the calculated Schwartz score:

•For patients with an intermediate or high Schwartz score (ie, score >1), we perform genetic testing.

•For those with a low Schwartz score (ie, score ≤1), we do not usually perform genetic testing; however, testing may be appropriate for certain patients who were identified to have a reversible cause of QT prolongation during the initial evaluation (see 'Evaluation of all patients' above). In such patients, we perform genetic testing if they meet at least two of the following criteria, which are associated with the presence of a pathogenic variant on genetic testing [24]:

-Age ≤40 years of age

-Personal history concerning for arrhythmia (eg, syncope, torsades de pointes, cardiac arrest)

-QTc >440 ms after the reversible cause of QT prolongation has been removed

We do not perform genetic testing on patients who meet fewer than two of these criteria.

Our recommendations for risk stratification and genetic testing are generally in accord with those of professional societies [44-46]. In the future, artificial intelligence may prove useful for risk stratification [47,48].

Interpreting the genetic test results — The diagnosis of congenital LQTS is established by a positive genetic test (ie, presence of a known pathogenic variant). However, in certain circumstances, LQTS might still be present in a patient with a negative genetic test. The genetic test result must be interpreted in the clinical context (eg, patient and family history, electrocardiographic findings) (algorithm 1). The following cases illustrate this point:

●A 16-year-old patient has marked QT prolongation (QTc >500 ms) and a sibling who died suddenly. Their clinical risk of LQTS is high. If their genetic test results were negative, we would suspect they have LQTS due to an as-yet-unidentified genetic variant and would manage them for presumed LQTS. (See "Congenital long QT syndrome: Treatment".)

●An 18-year-old athlete without a significant personal or family history has QTc of 470 ms and an unremarkable exercise stress test. Their clinical risk of LQTS is intermediate. If their genetic test results were negative, the likelihood of congenital LQTS would be low, and they would not receive a diagnosis of LQTS.

Interpretation of genetic test results is complex and is discussed in detail separately. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)", section on 'Implications for management'.)

DIFFERENTIAL DIAGNOSIS — 

In patients with suspected congenital long QT syndrome (LQTS), the major differential diagnosis is acquired LQTS, of which there are many causes (eg, metabolic abnormalities, drugs). Most patients with QT prolongation who are not diagnosed with congenital LQTS have acquired LQTS. Acquired LQTS can be differentiated from congenital LQTS by history, physical examination, and laboratory testing. (See 'History and physical' above and 'Laboratory tests' above and 'Address reversible causes' above.)

If a cause of acquired LQTS is not identified and the QTc is only slightly prolonged (ie, 10 to 20 ms greater than the 99^th percentile, which is QTc ≥460 ms in prepubertal patients, QTc ≥470 ms in postpubertal males, ≥480 ms in postpubertal females), the patient may simply be an outlier.

High levels of physical training may cause QTc prolongation, especially in teenagers [49,50]. Complete detraining for three to four months generally normalizes these ECG findings; however, we do not routinely ask patients to detrain. Rather, we reserve this suggestion for patients with marked QT prolongation and those with a concerning personal or family history.

POSTDIAGNOSTIC EVALUATION — 

All patients with an established diagnosis of congenital LQTS should undergo periodic surveillance testing with an electrocardiogram (ECG), exercise treadmill test (ETT), and 24-hour ambulatory ECG monitor to assess the risk of arrhythmias and optimize treatment. In one observational study of 946 patients with congenital LQTS, yearly risk assessment led to fewer implantable cardioverter-defibrillator implants without increasing life-threatening arrhythmias [51].

Our frequency of monitoring depends on the patient’s age and whether the patient has a history of symptomatic arrhythmia (eg, sudden cardiac arrest, cardiogenic syncope):

●For adult or pediatric patients with a history of symptomatic arrhythmia, we perform surveillance testing annually.

●For adult patients without a history of symptomatic arrhythmia, we perform surveillance testing every three to five years.

●For pediatric patients without a history of symptomatic arrhythmia, we perform surveillance testing every one to two years.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Long QT syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●When to suspect congenital LQTS – The diagnosis of congenital long QT syndrome (LQTS) should be suspected in any patient ≤40 years of age who has one or more of the following clinical or historical features: personal history of abrupt syncope (ie, not vasovagal), resuscitated sudden cardiac arrest, torsades de pointes, generalized seizures, or unexplained motor vehicle accident; family history of premature sudden death (≤40 years of age and autopsy negative), unexplained motor vehicle accident, unexplained drowning, generalized seizures, or genetically proven LQTS; or corrected QT interval (QTc) above the 99^th percentile (ie, QTc ≥460 ms in prepubertal patients, QTc ≥470 ms in postpubertal males, ≥480 ms in postpubertal females). A normal QTc does not exclude congenital LQTS. (See 'When to suspect congenital LQTS' above.)

●Referral to a specialist – Patients with suspected LQTS should be referred to a specialist (eg, pediatric or adult cardiologist, heart rhythm specialist, or genetic cardiologist) with expertise in the diagnosis of LQTS. (See 'Referral to a specialist' above.)

●Evaluation of all patients – All patients suspected of congenital LQTS should undergo an initial evaluation to determine the likelihood of congenital LQTS and to exclude potential causes of acquired LQTS.

•We perform a detailed history, physical examination, and laboratory tests to determine whether the patient has a personal or family history suggestive of arrhythmia, as well as whether a reversible cause of acquired LQTS may be present. (See 'History and physical' above and 'Laboratory tests' above.)

•We assess the electrocardiogram (ECG) for QT prolongation and T wave abnormalities. (See 'Electrocardiogram' above.)

•We address potentially reversible causes of QT prolongation (eg, drugs, hypokalemia, acute myocardial infarction). The resolution of QT prolongation after the removal of provoking factors does not necessarily exclude congenital LQTS. (See 'Address reversible causes' above.)

•We perform exercise treadmill testing (ETT) and 24-hour ambulatory ECG monitoring to look for arrhythmias and ECG abnormalities that may increase the likelihood of congenital LQTS. (See 'Exercise testing' above and 'Ambulatory ECG monitoring' above.)

●Establishing the diagnosis – The diagnosis of congenital LQTS is made with genetic testing. Genetic testing is reserved for patients in whom congenital LQTS is still suspected after the initial evaluation has been performed. (See 'Genetic testing to establish the diagnosis' above.)

●Differential diagnosis – The differential diagnosis for congenital LQTS includes acquired LQTS and QT prolongation due to high levels of physical training. In addition, some healthy individuals have a QTc greater than the 99^th percentile. (See 'Differential diagnosis' above.)

●Postdiagnostic evaluation – Patients with established congenital LQTS should undergo periodic surveillance testing with ECG, ETT, and 24-hour ambulatory ECG monitoring. (See 'Postdiagnostic evaluation' above.)